This invention relates to a process for the preparation of organic boronic acid derivatives. This invention also relates to a process for covalently coupling organic compounds, in particular to a process for covalently linking organic compounds via formation of an organic boronic acid derivative and coupling to other organic compounds.
Processes for forming covalent bonds between organic compounds, both inter- and intra-molecular, are of particular importance to the synthetic organic chemist. Many such reactions are known, each requiring its own special reaction conditions, solvents, catalysts, ring activating groups etc. Some known types of coupling reactions include the Grignard reaction, Heck reaction and Suzuki reactions (N. Migaura and A. Suzuki, Chem. Rev. 1995, 95, 2457-2483).
Catalysts of palladium, its complexes and its salts are well recognised for activation of Cxe2x80x94H bonds towards coupling reactions. In this regard the Heck reaction of an aryl halide with an aryl or vinyl halide in the presence of palladium derivatives has been the subject of intensive study. However commercial development of the Heck reaction has not progressed as rapidly as could have been expected. Other Group VIII metal catalysts, such as platinum and nickel, have also been used to activate such carbon bonds.
Substituted bi- and tri-aryl compounds are of great interest to the pharmaceutical and agrochemical industries. A great number of these compounds have been found to possess pharmaceutical activity, while others have been found to be useful herbicides. There is also interest from the polymer industry in polymers prepared by the linking together of organic compounds.
Conventional methods for covalently linking aromatic rings, such as by reaction of an appropriate Grignard reagent, involve harsh conditions and are not suitable for aromatic rings with active hydrogen containing substituents. Substituents with active hydrogen atoms also can become involved in unwanted side reactions leading to undesirable products. Such substituents need to be protected prior to reaction. Boronic acid derivatives required for the Suzuki reaction are traditionally synthesized through highly reactive organo metallic intermediates. In view of the severity of the reaction conditions the range of substituents which could be present during the linking reaction was considerably limited, and the range of useful reaction media (solvents) was restricted to those which are generally expensive, difficult to remove and/or toxic.
Other difficulties associated with the known coupling reactions are the high temperatures required and the lack of control of the functionality of the products, leading to complex mixtures which can be difficult to separate.
It has now been found that organic boronic acid derivatives can be prepared by reacting an organic compound having a halogen or halogen-like substituent with a penta- or hexa-substituted diboron derivative. The organic boronic acid derivatives are useful in the preparation of covalently coupled organic compounds.
Accordingly, one aspect of the present invention provides a process for the preparation of an organic boronic acid derivative comprising reacting a penta- or hexa-substituted diboron derivative with an organic compound having a halogen or halogen-like substituent at a coupling position in the presence of a Group VIII metal catalyst, such that direct carbon to boron bond is formed between said coupling position and a boron-containing residue of the penta- or hexa-substituted diboron derivative.
Another aspect of the present invention provides a process for the preparation of an organic boronic acid derivative comprising:
(A) reacting a tetra-substituted diboron derivative with a nucleophile to form a penta- or hexa-substituted diboron derivative; and
(B) reacting the penta- or hexa-substituted diboron derivative with an organic compound having a halogen or halogen-like substituent at a coupling position in the presence of a Group VIII metal catalyst such that a direct carbon to boron bond is formed between said coupling position and a boron-containing residue of the penta- or hexa-substituted diboron derivative.
It has also been surprisingly found that the two steps, i.e. formation of the penta or hexa substituted diboron derivatives and the reaction of these derivatives with the organic compound can be performed in a single pot without isolation of the penta or hexa derivatives.
Accordingly, in particularly preferred aspect the invention provides a process for the preparation of an organic boronic acid derivative comprising:
(A) reacting a tetra-substituted diboron derivative with a nucleophile to form a penta or as hexa substituted diboron derivative; and
(B) reacting the penta- or hexa-substituted diboron derivative in situ with an organic compound having a halogen or halogen-like substituent at a coupling position in the presence of a Group VIII metal catalyst such that a direct carbon to boron bond is formed between said coupling position and a boron-containing residue of the penta or hexa substituted diboron derivative.
The reaction of the penta- or hexa-substituted diboron derivative with an organic compound having a halogen or halogen-like substituent in a coupling position allows for the formation of organic boronic acid derivatives, with only minor amounts of carbonxe2x80x94carbon coupled product formed. This process conveniently allows for the controlled formation of organic boronic acid derivatives and is therefore useful in controlling the formation of carbon to carbon bonds.
In a further aspect, the present invention provides a process for coupling a first organic compound having at a coupling position a halogen or halogen-like substituent and a second organic compound having at a coupling position a halogen or halogen-like substituent comprising:
(A) preparing an organic boronic acid derivative by reacting a penta- or hexa-substituted diboron derivative with said first organic compound in the presence of a Group VIII metal catalyst such that a direct carbon to boron bond is formed between said coupling position and a boron-containing residue of the penta or hexa substituted diboron derivative; and
(B) reacting the organic boronic acid derivative with said second organic compound in the presence of a suitable base and a Group VIII metal catalyst, such that a carbon to carbon bond is formed between the respective coupling positions of the organic compounds.
In a particularly preferred embodiment the three steps, i.e. formation of the penta- or hexa-substituted diboron derivative, the reaction of the derivative with the organic compound to form the organic boronic acid derivative, and the coupling of that derivative with another organic compound are performed in the one pot without isolation of intermediates
According to this aspect the invention provides a process for coupling a first organic compound having at a coupling position a halogen or halogen-like substituent and a second organic compound having at a coupling position a halogen or halogen-like substituent comprising:
(A) reacting a tetra-substituted diboron derivative with a nucleophile to form a penta or hexa substituted diboron derivative;
(B) preparing a boronic acid derivative by reacting the penta- or hexa-substituted diboron derivative in situ with said first organic compound in the presence of a Group VIII metal catalyst such that a direct carbon to boron bond is formed between said coupling position and a boron-containing residue of the penta- or hexa-substituted diboron derivative; and
(C) reacting the boronic acid derivative in situ with said second organic compound in the presence of a Group VIII metal catalyst and a suitable base such that a carbon to carbon bond is formed between the respective coupling position of the organic compounds.
Prior to step (C) it is preferable to decompose any unreacted tetra-, penta- or hexa-substituted diboron derivative by adding water and a suitable base.
The base should be such that it is strong enough to break the boron to boron bond of the diboron compounds. The base added is preferably one which is capable of catalysing the coupling reaction of step (C).
The term xe2x80x9ccoupling positionxe2x80x9d as used herein refers to a position on an organic compound at which coupling to an organic compound is desired. Each organic compound may have one or more, preferably between 1 and 6, coupling positions.
This process conveniently allows for the preparation of both symmetrical and unsymmetrical products by varying the organic compound which is coupled to the organic boronic acid derivative.
As used herein the term xe2x80x9corganic compound having a halogen or halogen-like substituent at a coupling positionxe2x80x9d refers to any organic compound having a carbon to halogen or carbon to halogen-like substituent bond at a position where coupling to the organic compound is desired. The organic compound may be aliphatic, olefinic, aromatic, polymeric or dendritic or any combination thereof. The organic compound may have one or more, preferably between 1 and 6, halogen or halogen-like substituents at coupling positions.
The terms xe2x80x9caromaticxe2x80x9d and xe2x80x9caromatic compound(s)xe2x80x9d as used herein refer to any compound which includes or consists of one or more aromatic or pseudoaromatic rings. The rings may be carbocyclic or heterocyclic, and may be mono or polycyclic ring systems. Examples of suitable rings include but are not limited to benzene, biphenyl, terphenyl, quaterphenyl, naphthalene, tetradyronaphthalene, 1-benzylnaphthalene, anthracene, dihydroanthracene, benzanthracene, dibenzanthracene, phenanthracene, perylene, pyridine, 4-phenylpyridine, 3-phenylpyridine, thiophene, benzothiophene, naphthothiophene, thianthrene, furan, pyrene, isobenzofuram, chromene, xanthene, phenoxathiin, pyrrole, imidazole, pyrazole, pyrazine, pyrimidine, pyridazine, indole, indolizine, isoindole, purine, quinoline, isoquinoline, phthalazine, quinoxaline, quinazoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, phenazine, isothiazole, isooxazole, phenoxazine and the like, each of which may be optionally substituted. The terms xe2x80x9caromaticxe2x80x9d and xe2x80x9caromatic compound(s)xe2x80x9d include molecules, and macromolecules, such as polymers, copolymers and dendrimers which include or consist of one or more aromatic or pseudoaromatic rings. The term xe2x80x9cpseudoaromaticxe2x80x9d refers to a ring system which is not strictly aromatic, but which is stablized by means of delocalization of xcfx80 electrons and behaves in a similar manner to aromatic rings. Examples of pseudoaromatic rings include but are not limited to furan, thiophene, pyrrole and the like.
As used herein, an xe2x80x9colefinicxe2x80x9d and xe2x80x9colefinic compoundxe2x80x9d as used herein refer to any organic compound-having at least one carbon to carbon double bond which is not part of an aromatic or pseudo aromatic system. The olefinic compounds may be selected from optionally substituted straight chain, branched or cyclic alkenes; and molecules, monomers and macromolecules such as polymers and dendrimers, which include at least one carbon to carbon double bond. Examples of suitable olefinic compounds include but are not limited to ethylene, propylene, but-1-ene, but-2-ene, pent-1-ene, pent-2-ene, cyclopentene, 1-methylpent-2-ene, hex-1-ene, hex-2-ene, hex-3-ene, cyclohexene, hept-1-ene, hept-2-ene, hept-3-ene, oct-1-ene, oct-2-ene, cyclooctene, non-1-ene, non-4-ene, dec-1-ene, dec-3-ene, buta-1,3-diene, penta-1,4-diene, cyclopenta-1,4-diene, hex-1,4, diene, cyclohexa-1,3-diene, cyclohexa-1,4-diene, cyclohepta-1,3-diene, cyclohepta-1,3,5-triene and cycloocta-1,3,5,7-tetraene, each of which may be optionally substituted. Preferably the straight chain branched or cyclic alkene contains between 1 and 20 carbon atoms.
In this specification xe2x80x9coptionally substitutedxe2x80x9d means that a group may or may not be further substituted with one or more groups selected from alkyl, alkenyl, alkynyl, aryl, halo, haloalkyl, haloalkenyl, haloalkynyl, haloaryl, hydroxy, alkoxy, alkenyloxy, aryloxy, benzyloxy, haloalkoxy, haloalkenyloxy, haloaryloxy, isocyano, cyano, formyl, carboxyl, nitro, nitroalkyl, nitroalkenyl, nitroalkynyl, nitroaryl, nitroheterocyclyl, amino, alkylamino, dialkylamino, alkenylamino, alkynylamino, arylamino, diarylamino, benzylamino, imino, alkylimine, alkenylimine, alkynylimino, arylimino, benzylimino, dibenzylamino, acyl, alkenylacyl, alkynylacyl, arylacyl, acylamino, diacylamino, acyloxy, alkylsulphonyloxy, arylsulphenyloxy, heterocyclyl, heterocycloxy, heterocyclamino, haloheterocyclyl, alkylsulphenyl, arylsulphenyl, carboalkoxy, carboaryloxy mercapto, alkylthio, benzylthio, acylthio, sulphonamido, sulfanyl, sulfo and phosphorus-containing groups.
The organic compound must include at least one halogen or halogen-like substituent at a coupling position to enable reaction with the penta- or hexa-substituted diboron derivative. Preferred halogen substituents include I, Br and Cl. Cl may also be used although Cl is generally less reactive to substitution by the penta- or hexa-substituted diboron derivative or organic boronic acid derivative. The reactivity of chloro substituted organic compounds can be increased by selection of appropriate ligands on the catalyst. The terms xe2x80x9chalogen-like substituentxe2x80x9d and xe2x80x9cpseudo-halidexe2x80x9d refer to any substituent which, if present on an organic compound, may undergo substitution with a penta- or hexa-substituted diboron derivative in the presence of a suitable catalyst to give an organic boronic acid derivative, or if present on an organic compound may undergo substitution with an organic boronic acid derivative to give a coupled product. Examples of halogen-like substituents include triflates and mesylates, diazonium salts, phosphates and those described in Palladium Reagents and Catalysts (Innovations in Organic Synthesis by J. Tsuji, John Wiley and Sons, 1995, ISBN 0-471-95483-7).
The process according to the present invention is especially suitable for coupling organic compounds containing substituents which are reactive with organometallic compounds, such as Grignard reagents or alkyl lithiums, therefore unsuitable for reacting using standard Grignard methodology unless these substituents are first protected. One such class of reactive substituents are the active hydrogen containing substituents. The term xe2x80x9cactive hydrogen containing substituentxe2x80x9d as used herein refers to a substituent which contains a reactive hydrogen atom. Examples of such substituents include but are not limited to hydroxy, amino, imino, acetyleno, carboxy (including carboxylato), carbamoyl, carboximidyl, sulfo, sulfinyl, sulfinimidyl, sulfinohydroximyl, sulfonimidyl, sulfoniimidyl, sulfonohydroximyl, sultamyl, phosphinyl, phosphinimidyl, phosphonyl, dihydroxyphosphanyl, hydroxyphosphanyl, phosphono (including phosphonato), hydrohydroxyphosphoryl, allophanyl, guanidino, hydantoyl, ureido, and ureylene. Of these substituents it is particularly surprising that the reaction can be conducted with hydroxy and amino substituents in view of their high reactivity. Carboxyl, sulfo and the like (i.e. acidic) substituents may require additional base. Other reactive substituents include trimethylsilyl.
In the above definitions, the term xe2x80x9calkylxe2x80x9d, used either alone or in compound words such as xe2x80x9calkenyloxyalkylxe2x80x9d, xe2x80x9calkylthioxe2x80x9d, xe2x80x9calkylaminoxe2x80x9d and xe2x80x9cdialkylaminoxe2x80x9d denotes straight chain, branched or cyclic alkyl, preferably C1-20 alkyl or cycloalkyl. Examples of straight chain and branched alkyl include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, amyl, isoamyl, sec-amyl, 1,2-dimethylpropyl, 1,1-dimethyl-propyl, hexyl, 4-methylpentyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 1,2,2,-trimethylpropyl, 1,1,2-trimethylpropyl, heptyl, 5-methoxyhexyl, 1-methylhexyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 4,4-dimethylpentyl, 1,2-dimethylpentyl, 1,3-dimethylpentyl, 1,4-dimethyl-pentyl, 1,2,3,-trimethylbutyl, 1,1,2-trimethylbutyl, 1,1,3-trimethylbutyl, octyl, 6-methylheptyl, 1-methylheptyl, 1,1,3,3-tetramethylbutyl, nonyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-methyl-octyl, 1-, 2-, 3-, 4- or 5-ethylheptyl, 1-, 2- or 3-propylhexyl, decyl, 1-, 2-, 3-, 4-, 5-, 6-, 7- and 8-methylnonyl, 1-, 2-, 3-, 4-, 5- or 6-ethyloctyl, 1-, 2-, 3- or 4-propylheptyl, undecyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8- or 9-methyldecyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-ethylnonyl, 1-, 2-, 3-, 4- or 5-propylocytl, 1-, 2- or 3-butylheptyl, 1-pentylhexyl, dodecyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9- or 10-methylundecyl, 1-, 2-, 3-, 4-, 5-, 6-, 7- or 8-ethyldecyl, 1-, 2-, 3-, 4-, 5- or 6-propylnonyl, 1-, 2-, 3- or 4-butyloctyl, 1-2-pentylheptyl and the like. Examples of cyclic alkyl include mono- or polycyclic alkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl and the like.
The term xe2x80x9calkoxyxe2x80x9d denotes straight chain or branched alkoxy, preferably C1-20 alkoxy. Examples of alkoxy include methoxy, ethoxy, n-propoxy, isopropoxy and the different butoxy isomers.
The term xe2x80x9calkenylxe2x80x9d denotes groups formed from straight chain, branched or cyclic alkenes including ethylenically mono-, di- or poly-unsaturated alkyl or cycloalkyl groups as previously defined, preferably C2-20 alkenyl. Examples of alkenyl include vinyl, allyl, 1-methylvinyl, butenyl, iso-butenyl, 3-methyl-2-butenyl, 1-pentenyl, cyclopentenyl, 1-methyl-cyclopentenyl, 1-hexenyl, 3-hexenyl, cyclohexenyl, 1-heptenyl, 3-heptenyl, 1-octenyl, cyclooctenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 1-decenyl, 3-decenyl, 1,3-butadienyl, 1,4, pentadienyl, 1,3-cyclopentadienyl, 1,3-hexadienyl, 1,4-hexadienyl, 1,3-cyclohexadienyl, 1,4-cyclohexadienyl, 1,3-cycloheptadienyl, 1,3,5-cycloheptatrienyl and 1,3,5,7-cyclooctatetraenyl.
The term xe2x80x9calkynylxe2x80x9d denotes groups formed from straight chain, branched or cyclic alkyne including alkyl and cycloalkyl groups as previously defined which contain a triple bond, w preferably C2-20alkynyl. Examples of alkynyl include ethynyl, 2,3-propynyl and 2,3- or 3,4-butynyl.
The term xe2x80x9cacylxe2x80x9d either alone or in compound words such as xe2x80x9cacyloxyxe2x80x9d, xe2x80x9cacylthioxe2x80x9d, xe2x80x9cacylaminoxe2x80x9d or xe2x80x9cdiacylaminoxe2x80x9d denotes carbamoyl, aliphatic acyl group and acyl group containing an aromatic ring, which is referred to as aromatic acyl or a heterocyclic ring which is referred to as heterocyclic acyl, preferably C1-20 acyl. Examples of acyl include carbamoyl; straight chain or branched alkanoyl such as formyl, acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 2,2-dimethylpropanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, heptadecanoyl, octadecanoyl, nonadecanoyl and icosanoyl; alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, t-pentyloxycarbonyl and heptyloxycarbonyl; cycloalkylcarbonyl such as cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl and cyclohexylcarbonyl; alkylsulfonyl such as methylsulfonyl and ethylsulfonyl; alkoxysulfonyl such as methoxysulfonyl and ethoxysulfonyl; aroyl such as benzoyl, toluoyl and naphthoyl; aralkanoyl such as phenylalkanoyl (e.g. phenylacetyl, phenylpropanoyl, phenylbutanoyl, phenylisobutylyl, phenylpentanoyl and phenylhexanoyl) and naphthylalkanoyl (e.g. naphthylacetyl, naphthylpropanoyl and naphthylbutanoyl]; aralkenoyl such as phenylalkenoyl (e.g. phenylpropenoyl, phenylbutenoyl, phenylmethacryloyl, phenylpentenoyl and phenylhexenoyl and naphthylalkenoyl (e.g. naphthylpropenoyl, naphthylbutenoyl and naphthylpentenoyl); aralkoxycarbonyl such as phenylalkoxycarbonyl (e.g. benzyloxycarbonyl); aryloxycarbonyl such as phenoxycarbonyl and napthyloxycarbonyl; aryloxyalkanoyl such as phenoxyacetyl and phenoxypropionyl; arylcarbamoyl such as phenylcarbamoyl; arylthiocarbamoyl such as phenylthiocarbamoyl; arylglyoxyloyl such as phenylglyoxyloyl and naphthylglyoxyloyl; arylsulfonyl such as phenylsulfonyl and napthylsulfonyl; heterocycliccarbonyl; heterocyclicalkanoyl such as thienylacetyl, thienylpropanoyl, thienylbutanoyl, thienylpentanoyl, thienylhexanoyl, thiazolylacetyl, thiadiazolylacetyl and tetrazolylacetyl; heterocyclicalkenoyl such as heterocyclicpropenoyl, heterocyclicbutenoyl, heterocyclicpentenoyl and heterocyclichexenoyl; and heterocyclicglyoxyloyl such as thiazolylglyoxyloyl and thienylglyoxyloyl.
The terms xe2x80x9cheterocyclicxe2x80x9d, xe2x80x9cheterocyclylxe2x80x9d and xe2x80x9cheterocyclxe2x80x9d as used herein on their own or as part of a group such as xe2x80x9cheterocyclicalkenoylxe2x80x9d, heterocycloxyxe2x80x9d or xe2x80x9chaloheterocyclylxe2x80x9d refer to aromatic, pseudo-aromatic and non-aromatic rings or ring systems which contain one or more heteroatoms selected from N, S, O and P and which may be optionally substituted. Preferably the rings or ring systems have 3 to 20 carbon atoms. The rings or ring systems may be selected from those described above in relation to the definition of xe2x80x9caromaticxe2x80x9d.
The term xe2x80x9carylxe2x80x9d as used herein on its own or as part of a group such as xe2x80x9chaloarylxe2x80x9d and xe2x80x9caryloxycarbonylxe2x80x9d refers to aromatic and pseudo-aromatic rings or ring systems composed of carbon atoms, preferably between 3 and 20 carbon atoms. The rings or ring systems may be optionally substituted and may be selected from those described above in relation to the definition of xe2x80x9caromaticxe2x80x9d.
The term xe2x80x9ctetra-substituted diboron derivativexe2x80x9d may refer to diboronic acid itself or an ester or other derivative of diboronic acid. Examples of suitable esters and derivatives include those of the formula (RX)2Bxe2x80x94B(RX)2 where R is hydrogen, optionally substituted alkyl or optionally substituted aryl or xe2x80x94B(XR)2 represents a cyclic group of formula 
where each X which can be the same or different, can be O, S(O)n where n is 1 or 2 or NRxe2x80x3 where Rxe2x80x3 is hydrogen or C1-C12 alkyl, Rxe2x80x2 is optionally substituted alkylene, optionally substituted arylene or other divalent group comprising linked aliphatic or aromatic moieties. Preferred tetra-substituted diboron derivatives include bis(pinacolato)diboron (the pinacol ester of -diboronic acid), bis(ethanediolato)diboron, bis(n-propanediolato)diboron and bis(neopentanediolato)diboron. The diboron ester derivatives may be made following the method of Brotherton et al. [R. J. Brotherton, A. L. McCloskey, L. L. Peterson and H. Steinberg, J. Amer. Chem. Soc. 82, 6242 (196); R. J. Brotherton, A. L. McCloskey, J. L. Boone and H. M. Manasevit, J. Amer. Chem. Soc. 82, 6245 (1960)]. In this process B(NMe2)3, obtained by reaction of BCl3 with NHMe2, is converted to BrB(NMe2)2 by reaction with a stoichiometric amount of BBr3. Reduction in refluxing toluene with sodium metal gives the diboron compound [B(NMe2)2]2 which, after purification by distillation, can be reacted with the alcohol (for example, pinacol) in the presence of a stoichiometric amount of HCl to give the desired ester product. Bis(neopentanediolato)diboron is described by Nguyen et al [Nguyen, P., Lesley, G., Taylor, N. J., Marder, T. B., Pickett, N/L/, Clegg, W., Elsegood, M. R. J., and Norman, N. C., Inorganic Chem. 1994, 33,4623-24]. Other suitable xe2x80x9ctetra-substituted diboron derivativesxe2x80x9d are those analogous to the esters above, but where O is substituted by S(O)2 where n is 1 or 2, or NRxe2x80x3 where Rxe2x80x3 is H or C1-C12 alkyl.
The xe2x80x9cpenta- or hexa-substituted diboron derivativexe2x80x9d refers to a diboron derivative having 5 or 6 substituents. It may be a further substituted tetra-substituted diboron derivative, as hereinbefore defined, or an alkali metal salt thereof, wherein one or both of the boron atoms of the tetra-substituted diboron derivative bear a further substituent resulting from reaction between tetra-substituted diboron derivative and a nucleophile. The term xe2x80x9cpenta- or hexa-substituted diboron derivativexe2x80x9d may also collectively refer to a mixture of further penta- or hexa-substituted diboron derivatives resulting from reaction between the tetra-substituted diboron derivative and greater than 1 and less than 2 molar equivalents of nucleophile. It is a further advantageous feature of the present invention that the process can be performed with mixtures of penta- and hexa-substituted diboron derivatives.
Suitable examples of penta- or hexa-substituted diboron derivatives are of general formulae (i) and (ii) 
wherein M is a counterion and Nu is a nucleophile. Preferably M is a Group I or Group II metal ion. For penta- or hexa-substituted diboron derivatives of formula (i), where M is a monovalent Group I metal ion, each M may be the same or different.
Each Nu may be the same or different and may be a strong nucleophile, such as hydroxide, alkoxide, phenoxide, alkylamino or amino, alternatively the nucleophile may be a complex anion such as that from acacH formed by loss of a proton from an OH, or other anions formed by loss of a proton from OH, CH, SH or NH and may be monodentate or bidentate. It should be able to stabilise the monoboron moiety released in the boron carbon coupling reaction; most preferred Nu are methoxide, ethoxide, n-propoxide, i-propoxide, n-butoxide, t-butoxide, dimethylamino, diethylamino, diisopropylamino, fluoride, cyano or thiolate. Examples of preferred bidentate nucleophiles include those derived from ethylene glycol, ethanolamine or ethylenediamine.
Examples of chiral nucleophiles include those generated from (S)-(xe2x88x92)-1-phenylethanol; (R)-(+)-1-phenylethanol; (xe2x88x92)-1,2:5,6-Di-O-isopropylidene-xcex1-D-glucofuranose; (+)-1,2:5,6-Di-O-isopropylidene-D-mannitol; (S)-(+)-1,2-O-Isopropylidene-glycerol; (R)-(xe2x88x92)-1,2-O-Isopropylidene-glycerol; (+)-2,3-O-Isopropylidene-L-threitol; (xe2x88x92)-2,3-O-Isopropylidene-D-threitol; (S)-(+)-Methyl 3-hydroxy-2-methylpropionate; (S)-(xe2x88x92)-Methyl lactate; (R)-(xe2x88x92)-Methyl 3-hydroxy-2-methylpropionate; (S)-(+)-1-Amino-2-propanol; (R)-(xe2x88x92)-1-Amino-2-propanol; (+)-2,3-O-Isopropylidene-1,1,4,4-tetraphenyl-D-threitol; and (xe2x88x92)-2,3-L-Isopropylidene-1,1,4,4-tetraphenyl-L-threitol.
Each X, which can be the same or different, can be O, S(O)., where n is 1 or 2 or NRxe2x80x3 where Rxe2x80x3 is hydrogen or C1-C12 alkyl, and each R may be the same or different and is independently selected from hydrogen, optionally substituted alkyl, optionally substituted aryl or 
represents a cyclic group of the formula 
where X, Nu and Rxe2x80x2 are as previously defined.
The counterion M may be co-ordinated with a compound to further solubilize the base in a particular solvent, for example, crown ethers and cyclams.
The penta- on hexa-substituted diboron derivatives may be chiral compounds, and may have an enantiomeric excess of one or more enantomers or isomers relative to others. The chirality may be derived from any one or more of the substituents of the penta- or hexa-substituted diboron derivatives. The derivatives may be prepared from a suitable tetra-substituted diboron compound, or the chirality may be introduced using a chiral nucleophile to form the penta- or hexa-substituted diboron derivative. Chiral compounds can be used to advantage to produce chiral products.
Some of these penta- and hexa-substituted diboron derivatives are novel and represent a further aspect of the present invention.
The term xe2x80x9cboron-containing residuexe2x80x9d as used herein refers to a group of the general formula
B(XR)2 
wherein X and R are as defined above.
The term xe2x80x9cGroup VIII metal catalystxe2x80x9d as used herein refers to a catalyst comprising a metal of Group 8 of the periodic table described in CRC Handbook of Chemistry and Physics, 64th edition, 1983-1984, CRC Press. Examples of such metals include Ni, Pt, Pd and Co. Preferably the catalyst is a palladium catalyst as described below, although analogous catalysts of other Group VIII metals may also be used. Examples of suitable Ni catalysts include nickel black, Raney nickel, nickel on carbon and nickel clusters or a nickel complex. Examples of suitable Pt catalysts include-platinum black, platinum on carbon and platinum clusters or a platinum complex. The Group VIII metal catalyst may additionally include other metals. Examples of suitable cobalt catalysts include COCl2(dppf), CoCl2(PPh3)2, CoCl2[PPh2(CH2)3PPh2], and CoCl2[PPh2(CH2)4PPh2].
Examples of suitable palladium catalysts include but are not limited to Pd3(dba)3, PdCl2, Pd(OAc)2, PdCl2(dppf)CH2Cl2, Pd(PPh3)4 and related catalysts which are complexes of phosphine ligands, (such as (Ph2P(CH2)nPPh2) where n is 2 to 5, P(o-tolyl)3, P(i-Pr)3, P(cyclohexyl)3, P(o-MeOPh)3, P(p-MeOPh)3, dppp, dppb, TDMPP, TTMPP, TMPP, TMSPP, 2-(di-t-butylphosphino)biphenyl, (R,R)-Me-DUPHOS, (S,S)-Me-DUPHOS, (R)-BINAP, (S)-BINAP, and related water soluble phosphines), related ligands (such as triarylarsine, triarylantimony, triarylbismuth and others as described by W. A. Herrmann and C. Kxc3x6cher, Angew. Chem. Int. Ed. Engl. 1997, 36, 2162-2187), phosphite ligands (such as P(OEt)3, P(O-p-tolyl)3, P(O-o-tolyl)3, P(O-iPr)3, tris(2,4-di-t-butylphenyl)phosphite and other examples described in the STREM Catalogue No. 18 (Chemicals for Research: metals, inorganics and organometallics 1999-2001)) and other suitable ligands including those containing P and/or N atoms for coordinating to the palladium atoms, (such as for example pyridine, alkyl and aryl substituted pyridines, 2,2xe2x80x2-bipyridyl, alkyl substituted 2,2xe2x80x2-bipyridyl and bulky secondary or tertiary amines), and other simple palladium salts either in the presence or absence of ligands. The palladium catalysts include palladium and palladium complexes supported or tethered on solid supports, such as palladium on carbon, as well as palladium black, palladium clusters, palladium clusters containing other metals, and palladium in porous glass as described in J. Li, A. W-H. Mau and C. R. Strauss, Chemical Communications, 1997, p1275. The same or different palladium catalysts may be used to catalyse different steps in the process. The palladium catalyst may also be selected from those described in U.S. Pat. No. 5,686,608. In certain reactions there are advantages in using ligands with altered basicity and/or steric bulk.
Suitable catalysts also include metallocyclic compounds and compounds that can form metallocyclic species in situ in the reaction medium.
The catalysts according to the present invention may be prepared in situ. For example catalysts consisting of phosphine complexes of palladium can be prepared in situ by addition of a palladium (II) salt such as the acetate and the desired mono- or di-phosphine in a ratio such that the Pd/P atom ratio is approximately 1:2. Arsines, such as for example bis(diphenylarsino) ethane and the like can also be used in conjunction with Pd to make active catalysts for the boronation of aryl halide type species.
The process may be performed in any suitable solvent or solvent mixture provided that it is anhydrous. Examples of such solvents include amides of the lower aliphatic carboxylic acids and lower aliphatic secondary amines, DMSO, aromatic hydrocarbons, nitromethane, acetonitrile, benzonitrile, ethers, polyethers, cyclic ethers, lower aromatic ethers, lower alcohols, and their esters with the lower aliphatic carboxylic acids, pyridine, alkylpyridines, cyclic and the lower secondary and tertiary amines, and mixtures thereof, including mixtures with other solvents. In a preferred embodiment of the invention the process is performed in a protic solvent. Examples of suitable protic solvents include lower alcohols. Most preferably the solvent is ethanol, methanol, isopropanol or mixtures thereof and with other solvents.
The temperature at which each step of the process according to the invention is conducted will depend on a number of factors including the desired rate of reaction, solubility and reactivity of the reactants in the selected solvent, boiling point of the solvent, etc. The temperature of the reaction will generally be in the range of xe2x88x92100 to 250xc2x0 C. In a preferred embodiment the process is performed at a temperature between 0 and 80xc2x0, more preferably between 0 and 40xc2x0 C.
The terms xe2x80x9cnucleophilexe2x80x9d and xe2x80x9cNuxe2x80x9d as used herein refer to a compound which, when present in the reaction mixture, is capable of nucleophilically reacting with a xe2x80x9ctetra-substituted diboron derivativexe2x80x9d to form a xe2x80x9cpenta- or hexa-substituted diboron derivativexe2x80x9d as hereinbefore defined. It is also preferable that a nucleophile is chosen which is soluble in the solvent to which it is added. Examples of xe2x80x9cnucleophilesxe2x80x9d include hydroxides, fluorides, cyanides and thiolates of Li, Na, K, Rb, Cs, ammonium and the group II metals Mg, Ca, and Ba, and their alkoxides and phenoxides, thallium hydroxide, alkylammonium hydroxides and as well as amides such as LiNMe2 and NaNH2. Some of these nucleophiles may be used in conjunction with a phase transfer reagent, such as for example tetraalkylammonium salts or the crown ethers. Nucleophiles that may be used also includes alkali metal salts of potentially chelating ligands, for example acetylacetone.
Examples of xe2x80x9csuitable basesxe2x80x9d for catalysing the reaction between the organic boronic acid derivative and a further organic compound include the bases listed above as well as caesium carbonate, and potassium carbonate.
As used herein the term xe2x80x9corganic boronic acid derivativexe2x80x9d refers to the product of the Group VIII metal catalysed reaction between an organic compound having a halogen or halogen-like substituent at a coupling position and a xe2x80x9cpenta- or hexa-substituted diboron derivativexe2x80x9d, the product including a carbon to boron bond between the coupling position and a boron-containing residue of the penta- or hexa-diboron derivative. The term includes organic boronic acids, as well as their esters and other derivatives.
Thus, in another aspect of the invention there is provided a process for preparing an organic boronic acid derivative comprising reacting a penta- or hexa-substituted diboron derivative with an organic compound having a halogen or halogen-like substituent and an active hydrogen containing substituent in the presence of a Group VIII metal catalyst.
In a further aspect of the invention, where the organic boronic acid derivative is an ester, there is provided a process for the preparation of an organic boronic acid by the hydrogenolysis or hydrolysis, using established procedures, of the organic boronic acid derivative obtained as hereinbefore described.
The process according to the present invention is applicable to chemistry on solid polymer support or resin bead in the same manner as conventional chemistry is used in combinatorial chemistry and in the preparation of chemical libraries. Thus a suitable organic compound having a halogen or halogen-like substituent at a coupling position which is chemically linked to a polymer surface may be reacted with an organic boronic acid derivative in the presence of a palladium catalyst and a suitable base to form a coupled product linked to the surface of the polymer. Excess reagents and by-products may then be washed away from the surface leaving only the reaction product on the surface. The coupled product may then be isolated by appropriate cleavage of the chemical link from the polymer surface. The process is also possible using the alternative strategy of reacting an organic compound or an organic compound having a halogen or halogen-like substituent linked to a polymer surface with a penta- or hexa-substituted diboron derivative in the presence of a suitable catalyst to form an organic boronic acid derivative chemically linked to the polymer surface. This derivative may then be reacted with an organic compound having a halogen or halogen-like substituent at a coupling position in the presence of a Group III metal catalyst and a suitable base to prepare the coupled product chemically linked to the polymer. Excess reactants and by-products may be removed by suitable washing and the coupled product may be isolated by chemically cleaving the link to the polymer.
In accordance with the present invention it is also possible to directly functionalise the surface of a polymer, e.g. polystyrene, with a halogen, or halogen-like substituent and then convert this functionalised surface to an organic boronic acid derivative surface by reaction of the functionalised polymer with a penta- or hexa-substituted diboron derivative in the presence of a suitable catalyst. The organic boronic acid derivative surface may then be reacted with any suitable organic compound having a halogen or halogen-like substituent. If the organic compound contains other functional groups, for example carboxylic ester, they may be used as linking groups to further extend the chemical reactions applied to the polymer surface.
The term xe2x80x9clinking groupxe2x80x9d as used herein refers to any chain of atoms linking one organic group to another. Examples of linking groups include polymer chains, optionally substituted alkylene group, carboxylic esters and any other suitable divalent group.
It is also possible to prepare polyorganic compounds or other polymers by reaction of organic compounds having more than one halogen or halogen-like substituent. Such organic compounds may be reacted with a penta- or hexa-substituted diboron derivative in the presence of a palladium catalyst to form an organic boronic acid derivative having more than one boron functionality. These derivatives may be reacted with organic compounds or organic compounds having more than one halogen or halogen-like substituent to form a polymer. If the organic compound has three or more halogen or halogen-like substituents which react with the penta- or hexa-substituted diboron derivative then it is possible to prepare dendritic molecules in accordance with the process of the present invention.
The organic compound may be separate molecules or may be linked together such that the organic boronic acid derivative formed after reaction with the penta- or hexa-substituted diboron derivative is able to react at a coupling position located elsewhere in the molecule so as to provide for an intramolecular reaction, such as a ring closure reaction. Similarly the process according to the invention allows intramolecular linking to occur within different organic compounds bearing halogen or halogen-like substituents located at different parts of the molecule. Reaction of one halide substituent with a second penta- or hexa-substituted diboron derivative to form an organic boronic acid derivative allows reaction of that derivative with the halide substituent on the other compound to thereby link the organic compounds.
The process according to the invention is also useful for the preparation of reactive intermediates which are capable of taking part in further reactions or rearrangements. These reactive intermediates may be the organic boronic acid derivative or the coupled products. For example, aryl organic boronic acid derivatives may take part in one or more of the palladium catalysed reactions of aryl boron compounds described by Miyaura and Suzuki in Chem. Rev. 1995, 95 2457-2483.
The present invention allows the formation of organic boronic acid derivatives under exceptionally mild conditions. It is possible to form desired products in good yield at room temperature and below, and with functionalities which may be susceptible to attach by free bases and/or nucleophiles.
The process according to the present invention allow the linking of organic compounds under mild conditions and avoids the use of expensive, difficult to remove and/or toxic reagents and solvents. In this regard boron and boron compounds are generally non-toxic. The reactions may also be performed in relatively cheap solvents such as methanol and ethanol and, in view of the improved control over the reaction steps, it is envisaged that it would be possible to perform the reactions on an industrial scale. The process also allows the linking of organic compounds which contain active hydrogen substituents without the need to protect those substituents during the reaction.
The following examples are provided to illustrate some preferred embodiments of the invention. However it is to be understood that the following description is not to supersede the generality of the invention previously described.